9,10-Dihydro-9,10-methanoanthracene N-oxide derivatives

ABSTRACT

9,10-Dihydro-9,10-methanoanthracene N-oxide derivatives represented by the formula: ##STR1## wherein A represents a straight or branched C 1  -C 6  alkylene; R 1  and R 2  each represents C 1  -C 4  alkyl or phenyl-C 1  -C 4  alkyl, or ##STR2## represents the group ##STR3## and X represents methylene, hydroxymethylene, C 1  -C 4  alkyl ##STR4## or hydroxy-C 1  -C 4  alkyl ##STR5## and their pharmaceutically acceptable acid addition salts which are useful as anti-depressants, tranquilizers, or anti-epileptics.

This application is a divisional, of copending application Ser. No.750,630, filed on Dec. 15, 1976 and now U.S. Pat. No. 4,153,629.

The present invention relates to 9,10-dihydro-9,10-methanoanthraceneN-oxide derivatives and to the production thereof. More particularly,this invention relates to 9,10-dihydro-9,10-methanoanthracene N-oxidederivatives represented by the formula: ##STR6## wherein A represents astraight or branched C₁ -C₆ alkylene; R¹ and R² each represents C₁ -C₄alkyl or phenyl-C₁ -C₄ alkyl, or ##STR7## represents the group ##STR8##and X represents methylene, hydroxymethylene, C₁ -C₄ alkyl ##STR9## orhydroxy-C₁ -C₄ alkyl ##STR10## and their acid addition salts, which areuseful as antidepressants, tranquilizers, or anti-epileptics.Furthermore, it relates to the production of the above compounds (I).

In the above definition, the straight or branched C₁ -C₆ alkyleneinvolves methylene, ethylene, propylene, trimethylene, tetramethylene,2-methyl-tetramethylene, 2-ethyl-tetramethylene, pentamethylene, andhexamethylene. The C₁ -C₄ alkyl includes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and t-butyl.

The preferred significance for A is C₃ -C₄ alkylene. The preferredsignificance for each R¹ and R² is C₁ -C₃ alkyl, especially methyl.

The compounds represented by the formula (I) may form pharmaceuticallyacceptable salts with a variety of inorganic or organic acids. Suchsalts include the hydrochloride, sulfate, nitrate, phosphate,thiocyanate, acetate, succinate, oxalate, maleate, malate, phthalate,methanesulfonate, and salicylate.

The objective compounds of this invention can be prepared by severalmethods, one of which is shown by the following scheme: ##STR11##wherein B represents a reactive group (e.g. halogen, a residue ofester); R^(1') and R^(2') each represents C₁ -C₄ alkyl or phenyl-C₁ -C₄alkyl, or R^(1') ##STR12## represents the group ; X' representsmethylene, hydroxymethylene, C₁ -C₄ alkyl-N═ or hydroxy-C₁ -C₄ alkyl-N═; and A, R¹ and R² each is as defined above.

The starting compound (IV), for example,9,10-dihydro-9,10-methano-9-anthrylcarbonyl chloride (IVa) is preparedby using benzonorbornadiene-1-carboxylic acid (VI) [Chenier et al., J.Org. Chem., 38, 4350 (1973)] as in the following scheme: ##STR13## Otherstarting compounds, for example,9,10-dihydro-9,10-methano-9-anthrylacetyl chloride can be prepared bysubjecting 9,10-dihydro-9,10-methano-9-anthrylcarbonyl chloride (IVa) toa conventional procedure for increasing the carbon chain, such as theArndt-Eistert reaction.

The first step of this invention is carried out by reacting the startingcompound (IV) with the compound (V), if necessary, in an excess amountin a solvent (e.g. chloroform, methylene chloride, dimethylformamide,dioxane) at room temperature or under cooling. Examples of the compound(V) are dimethylamine, diethylamine, methylethylamine,methylbenzylamine, piperidine, 4-hydroxypiperidine, N-methylpiperazine,and N-(2-hydroxyethyl)piperazine.

The second step of the process is carried out by reducing the amide(III) with a metallic hydride complex such as lithium aluminum hydrideor potassium aluminum hydride in an inert solvent (e.g. tetrahydrofuran,dioxane, ether) with warming.

Thus-obtained amine derivative (II) is subjected to N-oxidation in thethird step. The third step is carried out by treating the amine (II)with an N-oxidizing agent (e.g. hydrogen peroxide, perphthalic acid,peracetic acid) in a suitable solvent (e.g. methanol, acetic acid,acetone, chloroform, dimethylformamide) at room temperature or undercooling or heating.

The 9,10-dihydro-9,10-methanoanthracene N-oxide derivatives may beconverted into pharmaceutically acceptable acid addition salts asmentioned above.

The 9,10-dihydro-9,10-methanoanthracene N-oxide derivatives (I) andtheir acid addition salts are useful as anti-depressants, tranquilizers,and anti-epileptics. The pharmacological test examined by the followingmethods shows that9-(3-dimethylaminopropyl)-9,10-dihydro-9,10-methanoanthracene N-oxide isas potent in antagonism is reserpine ptosis as imipramine, acommercially available anti-depressant, but about 4 times less toxic inthe acute toxicity than the drug.

Test Method

Anti-reserpine ptosis: This test was effected on a group of 10 femaleWistar rats, their body weight ranging from 200 to 230 g. A prescribedamount of the test compound was orally administered, and 30 minuteslater reserpine (5 mg/kg) was intraperitoneally administered. After thelapse of 4 hours, the effect of the test compound on thereserpine-induced ptotic symptom was observed in 9 orders. [Rubin etal., J. Pharmacol. exp. Therap., 120, 125 (1957)]. Acute toxicity: Thetest compound was orally administered to DS male mice in differentsingle doses. For each dose, 10 mice were used, their body weightranging from 20 to 23 g. The mice were observed for 72 hours after theadministration of the compound. The mortality was calculated by theBliss method [Bliss, Ann. Appl. Biol., 22, 134-307 (1935); Quant, J.Pharmacol., 11, 192 (1938)].

Other compounds of this invention exhibit similar pharmacologicalactivities.

Thus, the compounds (I) and their pharmaceutically acceptable acidaddition salts are useful in the treatment of, for example,manic-depressive insanity and epilepsy.

The 9,10-dihydro-9,10-methanoanthracene N-oxide derivatives (I) or theirpharmaceutically acceptable acid addition salts are applicable singly orin combination with pharmaceutically suitable carriers such as wheatstarch, corn starch, potato starch, gelatin, and the like. The choice ofcarriers is determined by the preferred route of administration, thesolubility of the substance and the standard pharmaceutical practice.Examples of pharmaceutical preparations are tablets, capsules, pills,suspensions, syrups, powders, and solutions. These compositions can beprepared in a conventional manner. A suitable dosage of the9,10-dihydro-9,10-methanoanthracene N-oxide derivatives (I) or theirpharmaceutically acceptable acid addition salts for human adults is inthe order of about 10 to 200 mg per day.

Presently preferred and practical embodiments of the present inventionare illustratively shown in the following examples.

EXAMPLE 1

(1) 9,10-Dihydro-9,10-methano-9-anthrylpropionic acid (585 mg) istreated with thionyl chloride to give9,10-dihydro-9,10-methano-9-anthrylpropionyl chloride. To a solution ofthe obtained chloride in methylene chloride is added a solution ofdimethylamine in methylene chloride under ice cooling. The resultantreaction mixture is washed with dilute hydrochloric acid and water inorder, dried, and evaporated to giveN,N-dimethyl-9,10-dihydro-9,10-methano-anthrylpropionamide (580 mg). Theproduct is recrystallized from a mixture of methylene chloride andhexane to give crystals melting at 179° to 180.5° C.

NMR (in CDC1₃) δ2.4 (d, 2H), 2.61 (m, 4H), 2.85 (s, 3H), 2.90 (s, 3H),4.25 (s, 1H), 6.8-7.4 (m, 8H).

IR (in CHCl₃) 1640 cm⁻¹

Anal. Calcd, for C₂₀ H₂₁ ON: C, 82.44; H, 7.26; N, 4.81 Found: C, 82.34;H, 7.16; N, 5.07.

(2) The above product,N,N-dimethyl-9,10-dihydro-9,10-methanoanthrylpropionamide (560 mg) isreduced with lithium aluminum hydride in tetrahydrofuran to give9-(3-dimethylaminopropyl)-9,10-dihydro-9,10-methanoanthracene, which istreated with hydrogen chloride in ether to yield a white precipitate.The precipitate is obtained by filtration. Recrystallization from amixture of methanol and ether gives9-(3-dimethylaminopropyl)-9,10-dihydro-9,10-methanoanthracenehydrochloride melting above 230° C.

Anal. Calcd. for C₂₀ H₂₄ NCl: C, 76.53: H, 7.71; N, 4.46; Cl, 11.30.Found: C, 76.28; H, 7.54; N, 4.57; Cl, 11.44.

(3) The free base of the product obtained above,9-(3-dimethylaminopropyl)-9,10-dihydro-9,10-methanoanthracene (964 mg),is dissolved in methanol (3 ml). To the solution is added a solution of30% hydrogen peroxide (395 mg) in methanol (3 ml) under ice cooling andstirring, and the resultant mixture is allowed to stand at roomtemperature for 2 days. The reaction mixture is evaporated under reducedpressure, and the residue is crystallized from benzene to give9-(3-dimethylaminopropyl)-9,10-dihydro-9,10-methanoanthracene N-oxide(950 mg). The substance is recrystallized from a mixture of methylenechloride and hexane to give crystals melting at 147° C. (decomp.).

NMR (in CDCl₃) δ2.3 (m, 4H), 2.4 (broad s, 2H), 3.1 (s, 6H), 3.3 (m,2H), 4.2 (s, 1H), 6.8-7.3 (m, 8H).

Anal. Calcd. for C₂₀ H₂₃ ON.1.4H₂ O; C, 75.39; H, 8.16; N, 4.40. Found:C, 75.40; H, 7.88; N, 4.68.

EXAMPLES 2-7

The following compounds are prepared by procedures similar to those inExaple 1.

    __________________________________________________________________________     ##STR14##                                                                    II                         I                                                   Ex.                                                                                       ##STR15##                                                                                    ##STR16##                                         No.                                                                              A        mp(°C.) mp(°C.)                                     __________________________________________________________________________    2  (CH.sub.2).sub.3                                                                        ##STR17##                                                                                    ##STR18##                                                     168-169        158-159(d)**                                       3  (CH.sub.2).sub.3                                                                        ##STR19##                                                                                    ##STR20##                                                     153.5-154.5    153-157(d)                                         4  (CH.sub.2).sub.3                                                                        ##STR21##                                                                                    ##STR22##                                                     121-122        203(d)**                                                       >230*                                                                 ##STR23##                                                                             N(CH.sub.3).sub.2>230*                                                                        ##STR24##                                         6  (CH.sub.2).sub.3                                                                        ##STR25##                                                                                    ##STR26##                                                     Oil            159.5-160.5**                                      7  (CH.sub.2).sub.3                                                                        ##STR27##                                                                                    ##STR28##                                                     Oil            145-146(d)                                         __________________________________________________________________________     Note:                                                                         *Hydrochloride                                                                **Picrate                                                                     (d) Decomposition                                                        

What is claimed is:
 1. A pharmaceutical composition comprising aneffective anti-depressant, tranquilizing or anti-epileptic amount of thecompound 9-(3-dimethylaminopropyl)-9,10-dihydro-9,10-methanoanthraceneN-oxide, or a pharmaceutically acceptable acid addition salt thereof,and a pharmaceutically suitable carrier.